Cardiovascular disease is the leading cause of mortality in western societies. Increased levels of circulating high-density lipoproteins (HDL) are thought to protect against the disease state by mediating cholesterol transport out of peripheral tissues. However, the molecular mechanisms underlying this process are incompletely characterized. The recent identification of the Tangier disease gene product (ABC1), which when mutated in human causes circulating HDL to drop to undetectable levels, has provided additional molecular insight into the process of reverse cholesterol transport. This application proposes to a structure-function analysis of ABC1 in terms of its cellular localization, protein-protein molecular description of ABC1 in relation to the ability of HDL to mobilize intracellular stores of cholesterol-esters will be helpful in the development of novel therapies for cardiovascular disease.